title: Phase I trial of fenretinide delivered orally in a novel organized lipid complex in patients with relapsed/refractory neuroblastoma: a report from the New Approaches to Neuroblastoma Therapy (NANT) consortium.
abstract: BACKGROUND
  A phase I study was conducted to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics of fenretinide (4-HPR) delivered in an oral powderized lipid complex (LXS) in patients with relapsed/refractory neuroblastoma.
  
  
  METHODS
  4-HPR/LXS powder (352-2,210 mg/m(2) /day) was administered on Days 0-6, in 21-day courses, by standard 3 + 3 design.
  
  
  RESULTS
  Thirty-two patients (median age = 8 years, range 3-27 years) enrolled with 30 evaluable for dose escalation. Prior therapies included stem cell transplantation/support (n = 26), 13-cis-retinoic acid (n = 22), (125/131) I-MIBG (n = 13), and anti-GD2 antibody (n = 6). 170+ courses were delivered. Course 1 DLTs were a Grade 3 (n = 1) alkaline phosphatase at 352 mg/m(2) /day. Other major toxicities were Grade 4 (n = 1) alkaline phosphatases on Courses 5 and 6 at 774 mg/m(2) /day, and Grade 3 (n = 1) ALT/AST elevation on Course 2 at 1,700 mg/m(2) /day. Of 29 response-evaluable patients, six had stable disease (SD) (4-26 courses); four with marrow- or bone disease-only had complete responses (CR) (10-46 courses). 4-HPR plasma levels were several folds higher (P < 0.05) than previously reported using capsular fenretinide. The Day 6 mean peak 4-HPR plasma level at 1,700 mg/m(2) /day was 21 µM. An MTD was not reached.
  
  
  CONCLUSIONS
  4-HPR/LXS oral powder obtained higher plasma levels, with minimal toxicity and evidence of anti-tumor activity, than a previous capsule formulation. A recommended phase II schedule of 4-HPR/LXS powder is 1,500 mg/m(2) /day, TID, on Days 0-6, of a 21-day course.
authors.affiliation: Department of Cell Biology & Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas; Department of Pediatrics, Texas Tech University Health Sciences Center, Lubbock, Texas; Department of Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Maurer
authors.forename: Min H
authors.initials: MH
authors.lastname: Kang
authors.forename: Judith G
authors.initials: JG
authors.lastname: Villablanca
authors.forename: Jitka
authors.initials: J
authors.lastname: Janeba
authors.forename: Susan
authors.initials: S
authors.lastname: Groshen
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Matthay
authors.forename: Paul M
authors.initials: PM
authors.lastname: Sondel
authors.forename: John M
authors.initials: JM
authors.lastname: Maris
authors.forename: Hollie A
authors.initials: HA
authors.lastname: Jackson
authors.forename: Fariba
authors.initials: F
authors.lastname: Goodarzian
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Shimada
authors.forename: Scarlett
authors.initials: S
authors.lastname: Czarnecki
authors.forename: Beth
authors.initials: B
authors.lastname: Hasenauer
authors.forename: C Patrick
authors.initials: CP
authors.lastname: Reynolds
authors.forename: Araz
authors.initials: A
authors.lastname: Marachelian
mesh_terms: D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009447:Neuroblastoma / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D017313:Fenretinide
keywords: LYM-X-SORB™; fenretinide; neuroblastoma; pediatric; powder